Mechanism-based prediction of particle size-dependent dissolution and absorption: cilostazol pharmacokinetics in dogs

A previously developed physiologically based pharmacokinetic (PBPK) model for gastro-intestinal transit and absorption was combined with a mechanistic dissolution model of the Noyes-Whitney type for spherical particles with a predefined particle size distribution. To validate the combined model, the plasma concentration-time curves for cilostazol obtained in beagle dogs using three different types of suspensions with varying particle diameters were simulated. In vitro dissolution information was also available for different formulations, but this data could only predict the in vivo outcome qualitatively. The mechanistic PBPK model, on the other hand, could predict the influence of the particle size on the rate and extent of absorption under both fasted and fed conditions accurately, and the gap between the in vitro dissolution data and the in vivo outcome could successfully be explained. We conclude that by integrating the processes of particle dissolution, gastro-intestinal transit and permeation across the intestinal epithelium into a mechanistic model, oral drug absorption from suspensions can be predicted quantitatively. The model can be applied readily to typical formulation development data packages to better understand the relative importance of dissolution and permeability and pave the way for successful formulation of solid dosage forms.